8dkw: Difference between revisions
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==Cryo-EM structure of cystinosin N288K mutant in a cytosol-open state at pH5.0== | |||
<StructureSection load='8dkw' size='340' side='right'caption='[[8dkw]], [[Resolution|resolution]] 3.09Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8dkw]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DKW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKW FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.09Å</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8dkw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dkw OCA], [https://pdbe.org/8dkw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dkw RCSB], [https://www.ebi.ac.uk/pdbsum/8dkw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dkw ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy. | |||
Structure and mechanism of human cystine exporter cystinosin.,Guo X, Schmiege P, Assafa TE, Wang R, Xu Y, Donnelly L, Fine M, Ni X, Jiang J, Millhauser G, Feng L, Li X Cell. 2022 Sep 29;185(20):3739-3752.e18. doi: 10.1016/j.cell.2022.08.020. Epub , 2022 Sep 15. PMID:36113465<ref>PMID:36113465</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8dkw" style="background-color:#fffaf0;"></div> | ||
[[Category: Li | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Li X]] | |||
[[Category: Schmiege P]] | |||
Latest revision as of 12:33, 17 October 2024
Cryo-EM structure of cystinosin N288K mutant in a cytosol-open state at pH5.0Cryo-EM structure of cystinosin N288K mutant in a cytosol-open state at pH5.0
Structural highlights
Publication Abstract from PubMedLysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy. Structure and mechanism of human cystine exporter cystinosin.,Guo X, Schmiege P, Assafa TE, Wang R, Xu Y, Donnelly L, Fine M, Ni X, Jiang J, Millhauser G, Feng L, Li X Cell. 2022 Sep 29;185(20):3739-3752.e18. doi: 10.1016/j.cell.2022.08.020. Epub , 2022 Sep 15. PMID:36113465[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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